Phagocytic cells and established cell lines from diphtheria sensitive and resistant species are being used to study the interaction of purified toxin at the level of the plasma membrane and in the cytosol. The ultimate objectives of the study are to identify biochemical differences (structural and/or enzymatic) which account either for resistance or susceptability to the lethal effect of diphtheria toxin. Current studies show that resistant cells adsorb and internalize radioiodinated toxin equally as well as do sensitive cells. Thus lack of receptor sites or exclusion mechanisms cannot account for resistance. Modifiers of toxin activity (ammonium chloride, sodium fluoride) and endocytosis (polyamino acids, cytochalasin B, iodoacetate) are in use to separate the important steps between the initial contact of protein toxin with the cell membrane and eventual death of the cell.